Introduction

Chiral organoboron play a substantial role in diverse fields of chemistry owing to their distinct geometric structures and unique electronic properties1,2,3. Tricoordinate boron compounds typically exhibit Lewis acidity due to an unoccupied p orbital, rendering them susceptible to nucleophilic attack4. This leads to formation of a sp3-hybridized boron center and enables the attainment of tetracoordinate boron compounds with a relatively stable tetrahedral geometry5,6,7,8. In fact, both tetracoordinate boron stereogenic center and C–B chiral axis have been found in natural products9, functional materials10,11, and chiral ligands12,13 (Fig. 1a). Although construction of carbon-stereogenic compounds at the α-position of organoborons has witnessed considerable progress, it remains highly challenging to create tetrahedral chiral-at-boron compounds in an enantiomeric form3,14,15,16,17,18,19,20,21. This is mainly due to the small size of the boron atom, the propensity of transmetalation of boron compounds in general, and the somewhat low configurational stability of these products (Fig. 1b, left)22,23.

Fig. 1: Asymmetric synthesis of boron–stereogenic and C–B axially chiral compounds.
Fig. 1: Asymmetric synthesis of boron–stereogenic and C–B axially chiral compounds.The alternative text for this image may have been generated using AI.
Full size image

a Chiral organoboron compounds as natural products and materials. b Enantioselective synthesis of Boron-Stereogenic and C–B axially chiral compounds. c Asymmetric transformation of (hetero atom-functionalized) alkynes to construct centrally and axially chiral compounds. d Enantioselective annulation of diverse arenes with boron-alkynes: access to boron-stereogenic and C–B axially chiral cycles (this work).

The rarity of asymmetric synthetic protocols to create B-stereogenic centers calls for development of novel synthetic methods. Given their availability and generally high reactivity, alkynes have been widely employed as unsaturated reagents toward construction of central chirality24,25,26,27. Particularly, metal-catalyzed enantioselective desymmetrization of alkynes (diynes) has emerged as an attractive strategy to create a tetra-substituted chiral center (Fig. 1c, left)28,29. In 2008, Tanaka reported desymmetrization of dialkynylphosphine oxides in [2 + 2 + 2] cycloaddition reactions, affording chiral-at-P arenes in excellent enantioselectivity30. In 2013, Zhou realized construction of a quaternary carbon center via copper-catalyzed azide-alkyne cycloaddition (CuAAC) using oxindole-based 1,6-heptadiynes as a prochiral diyne31. Later, Nozaki developed Rh-catalyzed desymmetrization of silicon-tethered diynes under mild conditions for construction of Si-stereogenic centers32. Despite the progress, compared with the extensive studies on the generation of tetrahedral C-33,34, Si-34,35,36,37, and P-38,39 stereocenters, enantioselective catalytic methods for constructing B-stereogenic compounds remains largely underexplored. Up to now, the He group reported the only example of desymmetrization of dialkynlborons through copper-catalyzed CuAAC reactions40, although desymmetrization of other tetracoordinate organoboron reagents at the boron center or a peripheral site has been recently accomplished by the Song group41 and the He group42,43,44.

On the other hand, axially chiral compounds have garnered continuous attention owing to their widespread applications as chiral ligands, organocatalysts, natural products, and pharmaceuticals45,46,47,48,49. In the regime of catalytic atroposelective synthesis, the vast majority of studies have focused on targets featuring a C–C chiral axis, likely due to the abundance of methods for construction of C–C bonds50,51,52. Recently, the flourish of C–N and N–N axially chiral (hetero)biaryls has further highlighted the significance and vitality of this regime53,54,55,56,57,58. In sharp contrast, studies toward asymmetric construction of C–B atropisomers remain heavily underexplored and considerably lags behind (Fig. 1b, right). This is primarily attributed to the low racemization barrier associated with a longer Csp2–B axis ( ~ 1.58 Å), compared to the typical Csp2–Csp2 bond length of 1.46 Å in biaryls (Fig. 1c, right)59. Despite the foreseeable challenges, encouraging progress has been made, and three synthetic strategies have been developed, namely, de novo C–B axis formation60, difunctionalization of alkynyl boron reagents61,62,63, and dynamic kinetic transformation of prochiral aromatics with a C–B bond13,64. In 2021, Song group reported the first atroposelective de novo synthesis of a C–B axially chiral platform via a Miyaura borylation reaction60. Alternatively, by employing an alkynylboron reagent, Song group61 and Wang group62 have independently developed [2 + 2 + 2] cycloaddition reaction between a diyne and an alkyne in excellent enantio- and regioselectivity. In addition, Song group also accomplished a nickel-catalyzed enantioselective radical relay reductive coupling reaction under mild conditions, which allowed facile formation of open-chain C–B axially chiral alkenylborons63. Besides these strategies, the Song group further developed atroposelective synthesis of C–B chiral biaryls via dynamic kinetic functionalization of the C–H or C–Br bond of biaryls bearing a preinstalled C–B bond13,64. Inspired by these studies, we focused on C–H activation-annulation reactions using both tetra- and tricoordinate boron-functionalized alkynes toward our target of boron-based chirality. Of note, these alkynes are intrinsically electron-poor and may pose compatibility issues during the annulation reactions initiated by C–H bond activation. As a continuation of our interest in studies of heteroatom-based chirality through C–H bond functionalization65,66,67,68,69,70,71, we herein report Rh(III)-catalyzed asymmetric coupling of arenes bearing a transformable chelating group with two classes of boron-functionalized alkynes, affording both boron-stereogenic heterocycles and C–B atropoisomers in excellent regio- and enantioselectivity (Fig. 1d).

Results

Optimization studies

Inspired by the stability of N,N-chelated tetracoordinate arylboron-diyne40, we initiated our exploration with optimization studies of the annulative coupling between boron-diyne 1 and N-tert-butyl-α-phenylnitrone66 (PBN, 2) under rhodium catalysis (Table 1). By employing a Cramer’s CpXRh(III) catalyst72 with AgSbF6 as a halide abstractor, thereby releasing a highly reactive Rh species to facilitate C–H bond activation, and HOPiv as an acid in dichloromethane, we found that the corresponding boron-stereogenic indenone was isolated in low yield and enantioselectivity (entry 1). A series of chiral catalysts were then examined, and the (R)-Rh3 proved to be superior to others in terms of activity (entries 1–5). When toluene was used as the solvent together with HOAc as the acid, the reaction proceeded with improved enantioselectivity to give 4 in moderate yield (entries 6–9). Further investigation of halide abstractor revealed that AgBF4 outperformed other common ones (yield up to 52%, ee up to 86%, entries 10−12). The employment of a catalytic amount of chiral carboxylic acid ((S)-CCA) further enhanced the enantioselectivity. Nevertheless, it was noted that both the racemic and enantioenriched acids facilitated the reaction and improved the enantioselectivity (entries 15−16). In addition, decreasing the temperature to 0 °C and extending the reaction time to 48 h afforded 4 in good yield and excellent enantioselectivity (94% ee, entry 17, Conditions A).

Table 1 Optimization studies of the synthesis of boron-stereogenic indenonesa
Full size table

The reaction scope

Having identified the optimal conditions (Conditions A), we next examined the scope of the N-tert-butyl-α-arylnitrone reagent (Fig. 2, up). Nitrones bearing a halogen group (F, Br) at the para-position demonstrated remarkable enantioselectivities (5 and 6, 91–96% ee). Regarding the coupling of a nitrone bearing a para ester group, slight modifications (AgOTf and MesCOOH) of the standard reaction conditions were made to ensure the production of the target product 7 in moderate yield and high enantioselectivity. Diverse meta substituents such as OMe, Cl, CF3, and CO2Me was also tolerated, affording the corresponding product in good yield with excellent enantioselective control (8–11, 46–73% yield, 90–95% ee). Overall, the reaction enantioselectivity was slightly influenced both by the electronic and steric effects of these substituents. An ortho-methoxy functionalized nitrone also proved applicable (12), although slightly reduced reactivity and enantioselectivity were observed (57% yield, 85% ee), likely due to the steric effect. Next, the scope of tetracoordinate boron-diyne was briefly evaluated. A variety of symmetrical diynes bearing diverse electron-donating and—withdrawing substituents in the benzene ring reacted smoothly to yield the target products with good reactivity and outstanding enantioselectivity (13–18). In addition, the alkyne terminus was successfully extended to a 2-thienyl rather than being confined to a phenyl ring (19, 86% yield, 96% ee). In addition, boron reagent bearing a substituted pyridine chelator was also tolerated (20–22). In comparisons, replacing the two methyl groups in the pyrrole ring with isopropyl groups led to lower enantioselectivity of the product (23, 66% yield, 74% ee). Further replacing the dimethyl groups with diphenyl groups, however, completely inhibited the reaction (see Supplementary Information Page S55 for details). The investigation of non-symmetrical diynes, however, failed because of lack of synthetic methods for this class of diyne.

Fig. 2: Scope of synthesis of two classes of boron–stereogenic compounds.
Fig. 2: Scope of synthesis of two classes of boron–stereogenic compounds.The alternative text for this image may have been generated using AI.
Full size image

[a] Reaction conditions A: 1 (0.12 mmol), 2 (0.10 mmol), (R)-Rh3 (4 mol%), AgBF4 (16 mol%) and CCA (50 mol%) in toluene (2 mL), 0 °C, 48 h. [b] AgOTf (16 mol%) and MesCOOH (2 equiv) was used. [c] Reaction conditions B: 1 (0.12 mmol), 3 (0.10 mmol), (R)-Rh3 (4 mol%), PhCOOAg (50 mol%) and HOAc (0.20 mmol) in toluene (2 mL), 40 °C, 24 h. Isolated yield. The enantioselectivity was determined by HPLC analysis using a chiral stationary phase.

To better explore the diversity of arene substrates in enantioselective desymmetrization-annulations, we applied N-OPiv benzamides bearing an internal oxidizing N–O bond as an arene source (Fig. 2, down)73. A series of catalysts, additives, and solvents were screened (see Supplementary Information Table S2 for details). It was found that the same Rh(III) catalyst sufficed with PhCOOAg (50 mol%) and HOAc (2 equiv) as the additives in toluene solvent at 40 °C (Conditions B), from which the desired [4 + 2] annulation product 24 was isolated in high yield (80% yield) and excellent enantioselectivity (91% ee). Such benzamides bearing various substituents such as alkyl, halogen, phenyl and CF3 group at different positions of the benzene ring all underwent efficient [4 + 2] annulation, yielding the desired tetracoordinate boron-attached isoquinolinones with a high level of enantioselectivities (25–30, 63–74% yield, 84–92% ee). Subsequently, the scope of the tetracoordinate B,N-diyne was investigated. Different substituents (methoxy, halogen, and fused benzene) in the alkyne terminus were tolerated, affording the desired products with excellent enantioselectivity (31–34), although introduction of electron-withdrawing group into this terminus generally caused poor reactivity. Moreover, the reaction also proceeded efficiently when an analogous enyne was employed (36, 65% yield, 82% ee). Of note, two diastereomers were observed in the NMR timescale for products 33, 34, and 36 bearing a relatively bulky C(isoquonolone)-Aryl/alkenyl group, which may cause partially restricted rotation along the B–C(sp2) bond. Introduction of a methyl (37 and 38) or two isopropyl groups (39) into the pyridine ring or the pyrazole ring, respectively, had marginal effect on the reaction efficiency and enantioselectivity, and other heteroarenes such as indole was also compatible, affording the target product with attenuated enantioselectivity (40, 83% ee). In addition, the N,N-chelator in the diyne was smoothly extended to a N,C chelator by replacing the pyrazole ring with a benzene ring, and corresponding product 41 was isolated in 68% yield and 89% ee. However, replacing the pyrazole ring with a thiophene only gave a nearly racemic product (42).

With the enantioenriched products 4 and 24 in hand, the absolute configuration of these products was ascertained by X-ray crystallographic analyses (CCDC 2410668 and CCDC 2410665, respectively) to be (R) at the boron stereogenic center. According to the geometric data of these two structures, the distance of the B1−N2 bond is consistently longer than that of the B1 − N1(pyrazole) bond, indicative of a weak dative B1−N2 bond. The tetrahedral character (THCDA) of the boron atom in products 4 and 24 has been calculated to be 72% and 65%, respectively, in light of the Hopfl’s equation with consideration of the six bond angles θ1−θ6 at the boron atom (Fig. 3)74. Experimentally, we carried out racemization studies for product indenone 16, and a ΔG≠rac = 31.7 kcal mol−1 was obtained at 100 °C in toluene. Under the same conditions, the energy barrier of isoquinolone 24 was measured to be ΔG≠rac = 28.5 kcal mol−1, further indicating the relatively low stereochemical stability of the tetracoordinate boron-stereogenic compounds. Here, the lower racemization barrier of 24 is ascribed to its reduced tetrahedral character, and the racemization barrier is essentially not correlated to the ring size (five versus six) of the resulting (hetero)cycle.

Fig. 3: Configuration analysis of tetracoordinate boron-stereogenic compounds.
Fig. 3: Configuration analysis of tetracoordinate boron-stereogenic compounds.The alternative text for this image may have been generated using AI.
Full size image

[a] Key bond lengths, angles and the tetrahedral character at the boron stereogenic center in compounds 4 and 24.

Having accomplished asymmetric synthesis of B-stereogenic aromatics, we then went on to investigate the construction of C−B axially chiral biaryls by annulation of arenes with sterically hindered boron-substituted alkynes by adopting a similar strategy of Rh(III)-catalyzed C−H bond activation (Fig. 4). The two classes of arenes displayed in Fig. 4 turned out to be inapplicable toward [4 + 2] annulation with an alkynyl-substituted BN aromatic compound (44). After extensive exploration of heteroarenes, N-methoxy-2-indolylcarboxamide (43) was identified as a suitable candidate which demonstrated high activity and regioselectivity. Its coupling with alkyne 44 afforded the desired atropisomer 45 (70% yield, 96% ee) with R-Rh4/AgSbF6 as a catalyst and Zn(OAc)2 as the base in ethyl acetate (Conditions C). The scope of this C−B atroposelective system was then explored (Fig. 4). Various substituents in the indole ring, such as alkyl, methoxy, and halogen at different positions are well compatible (46–52, 45–70% yield, 71–99% ee). The introduction of various substituents, such as alkyl group, halogen, and CF3, into the benzene ring of the alkyne terminus also allowed the isolation of the coupled products in excellent enantioselectivity (53–58). Furthermore, a pyrrole-based carboxymide was also amenable to the standard reaction conditions, affording C−B axially chiral product 59 in moderate yield and high enantioselectivity (88% ee). Replacing the N-iPr group in the BN aromatic ring with an N-benzyl caused decrease of the enantioselectivity (60, 82% ee). Further extension to N−Ph group was also successful, and product 61 was generated in 96% ee. In this case, 61 was isolated as two diastereomers (d.r. = 1.6:1) given the presence of an additional N-Ph axis (restricted rotation along the N−Ph bond). In contrast, an unprotected NH indole substrate failed to undergo any coupling, likely due to inhibitive N−N chelation. The absolute configuration of product 45 has been determined by X-ray crystallography (CCDC 2410664). Furthermore, racemization studies on a representative product 54 revealed a rotational barrier of 31.1 kcal mol−1, signifying relatively high configurational stability of the C−B axis rendered by the sterically hindered, densely fused heteroaryl group.

Fig. 4: Synthesis of C–B axially chiral compounds.
Fig. 4: Synthesis of C–B axially chiral compounds.The alternative text for this image may have been generated using AI.
Full size image

[a] Reaction conditions C: 43 (0.15 mmol), 44 (0.10 mmol), (R)-Rh4 (4 mol%), AgSbF6 (16 mol%), and Zn(OAc)2 (0.20 mmol) in EA (2 mL), 40 °C, 24 h, isolated yield. The ee was determined by HPLC analysis using a chiral stationary phase.

Synthetic applications

To further demonstrate the practicality of our protocol, the C−H activation-annulation of nitrones functionalized with a series of natural products or drug molecules was investigated. Thus, nitrone tethered to gemfibrozil (62), abietic acid (63), zingerone (64), citronellol (65), (L)-menthol (66), isophytol (67), pregnenolone (68), or cholesterol (69) all underwent smooth coupling with the gem-diyne 1. The corresponding boron-stereogenic indenone was obtained in excellent stereoselectivity (Fig. 5a), indicting the excellent function group compatibility of this coupling system. In addition, a representative product (R)−24 was synthesized in a mmol scale in 78% yield and 90% ee under a reduced catalyst loading (2 mol%). Treatment of 24 with MeI yielded the N-methylated product 70, and further addition of phenylmagnesium bromide to this isoquinolone afforded 1-arylisoquinolinium salt 71 in excellent yield upon acid work-up75. O-Triflation of isoquinolinone 24 using PhNTf2 gave 72, and subsequent Suzuki coupling or hydrodetriflation afforded isoquinolines 73 or 74, respectively, in high yield with only slight drease of the enantiopurity. Meanwhile, scale-up synthesis of C−B axially chiral compound 45 followed by bromination provided the indole-brominated derivative 76 in 82% yield and 93% ee with exclusive selectivity at the 6-position of the indole ring. The C-Br bond in 76 was further functionalized through diverse C−C cross-coupling reactions (77–79). Subsequently, Pd-catalyzed conversion of the bromide in 76 to a phosphine oxide 80 followed by standard reduction of the phosphine oxide afforded a trivalent phosphine 81 (90% ee), which may demonstrate potential for asymmetric catalysis as a ligand (Fig. 5b). Pd-catalyzed alkylation of allyl acetate using C–B axially chiral phosphine ligand 81 afforded product 84 in good yield with 46% ee, which may be attributed to the remote phosphine position relative to the chiral environment (Fig. 5c).

Fig. 5: Synthetic applications.
Fig. 5: Synthetic applications.The alternative text for this image may have been generated using AI.
Full size image

a Scope of [3 + 2] annulation of nitrones bearing a bioactive or drug moiety. aReaction conditions: nitrone (0.12 mmol), alkyne (0.10 mmol), (R)-Rh3 (4 mol%), AgBF4 (16 mol%) and CCA (50 mol%) in toluene (2 mL), 0 °C, 48 h; bnitrone (0.12 mmol), alkyne (0.10 mmol), (R)-Rh3 (4 mol%), AgOTf (16 mol%) and MesCOOH (2 equiv) in toluene (2 mL), 25 °C, 48 h. b Scale-up synthesis and synthetic transformations of a selected product. reaction conditions c: 72 (0.10 mmol), p-tolylboronic acid (0.20 mmol), Pd(PPh3)4 (4 mol%) and Na2CO3 (0.2 mmol) in toluene:EtOH:H2O (2 mL, 10:1:1), 60 °C, 12 h; Reaction conditions d: 72 (0.10 mmol), Pd(OAc)2 (5 mol%), dppf (10 mol%), HCOOH (0.25 mmol) and Et3N (0.3 mmol) in DMF (2 mL), 50 °C, 3 h. c Applications of chiral phosphine ligand.

Representative C−B axially chiral compounds (45, 50, 58, and 61) and boron-stereogenic heterocycles (28, 38, 72, and 73) were selected to explore their fundamental photophysical properties in solution (Fig. 6). Concentration effect in dichloromethane was first investigated to ensure the monomeric state (see Supplementary Information Figs. S1–S4 for details). All compounds showed good linear relationship between concentration and absorption in the range of 10−6 to 10−5 M. The fluorescence spectra did not show any change in peak pattern or wavelength, which also proved monomeric state in the tested concentration range. The strongest absorption bands of these compounds are centered around 325, 360, and 376 nm (45); 324, 367, and 387 nm (50); 326 nm and 363 nm (58); and 361 nm and 377 nm (61) (Fig. 6a and Table 2). Under identical concentration conditions, the boron-containing stereogenic heterocycles exhibit absorption peaks at 304, 328, and 407 nm (28); 302, 331, and 399 nm (38); 331 nm and 407 nm (72); and 328 nm and 407 nm (73) (Fig. 6b). Meanwhile, representative compounds from both the C–B axially chiral series and the boron stereogenic heterocycles show closely resembling absorption patterns, likely arising from localized π–π* transitions or charge transfer processes. In dichloromethane, compounds 45, 50, 58, and 61 emit blue fluorescence with quantum yields reaching up to 0.30, with emission maxima at 411 nm (45), 422 nm (50), 433 nm (58), and 412 nm (61). In contrast, boron stereogenic heterocycles 28, 38, 72, and 73 display bright yellow fluorescence with quantum yields up to 0.48, showing emission peaks at 517 nm (28), 502 nm (38), 529 nm (72), and 525 nm (73), respectively. Furthermore, circular dichroism (CD) measurements reveal that the strongest absorption dissymmetry factors (gabs) of these compounds range from −0.29 × 10−3 to −1.6 × 10−3 (Fig. 6c–f). Collectively, these readily accessible boron-based compounds, featuring both point and axial chirality alongside intense fluorescence, hold considerable promise for future applications in photoluminescent materials.

Fig. 6: Photophysical property investigations.
Fig. 6: Photophysical property investigations.The alternative text for this image may have been generated using AI.
Full size image

a Normalized UV–Vis absorption spectra and fluorescence emission spectra of 45, 50, 58, and 61 in DCM (λex = 350 nm, c = 1.0 × 10−5 M). The corresponding photographs showing their luminescence behavior in DCM under 365 nm UV light irradiation. b Normalized UV–vis absorption spectra and fluorescence emission spectra of 28, 38, 72, and 73 in DCM (λex = 330 nm, c = 1.0  × 10−5 M). The corresponding photographs showing their luminescence behaviour in DCM under 365 nm UV light irradiation. c CD spectra of 45, 50, 58, and 61 in DCM solution (c = 1 × 10–5 M). d gabs-wavelength curves of 45, 50, 58, and 61 in DCM. e CD spectra of 28, 38, 72, and 73 in DCM solution (c = 1 × 10–5 M). f gabs-wavelength curves of 28, 38, 72, and 73 in DCM.

Table 2 Photophysical properties of selected compounds (1 × 10−5 M in DCM)
Full size table

Mechanistic studies

A series of experimental studies have been briefly conducted to explore the mechanism of the coupling between the gem-diyne 1 and N-OPiv benzamide 3. Control experiments between this benzamide and isoquinolone 24 failed to give any further [4 + 2] annulation reaction under various reaction conditions (Fig. 7a). This observation indicated poor reactivity of this mono-alkyne caused by its steric effect toward the second [4 + 2] annulation, which also verified the necessity of a symmetrical tetracoordinate boron-diyne. Indeed, the twofold [4 + 2] product was not detected during the synthesis of product 24. To explore details of the C−H activation event, kinetic isotope effect was measured using two parallel reactions of 3 and 3-d5 (Fig. 7b). The kH/kD value at low conversions was found to be 2.6 based on 1H NMR analysis, suggesting that the C−H cleavage may be involved in the rate-limiting step or occurs prior to the turnover-limiting step. Subsequently, to better investigate the role of the catalyst, we carried out stoichiometric C−H activation reaction of amide and (R)-Rh3 in the presence of AgOAc, and then saturated it with PPh3. The 18-electron complex 85 was isolated in a good yield and was characterized by NMR spectroscopy (Fig. 7c), and the structure was assigned based on our previous report of a directly analogous complex65. Complex 85 exhibited catalytic activity when designated as a catalyst for the coupling of alkyne 1 and amide 3 (40% yield, 88% ee). Furthermore, we successfully synthesized a rhodium complex 87 from the stoichiometric reaction of an indolylcarboxamide and [RhCp*Cl2]2, which has been characterized by NMR analysis (Fig. 7e). The complex 87 exhibited moderate catalytic activity when employed in the coupling reaction between N-methoxy-2-indolylcarboxamide 43 and BN-alkyne 44 (35% yield), suggesting relevancy of C−H activation of this coupling reaction.

Fig. 7: Mechanistic studies.
Fig. 7: Mechanistic studies.The alternative text for this image may have been generated using AI.
Full size image

a control experiment. b kinetic isotope effect. c isolation of a catalytically relevant rhodium species for B-centered chirality. d viability of a rhodium complex as a catalyst precursor. e isolation of a catalytically relevant rhodium species. f viability of a rhodium complex as a catalyst precursor for C–B axial chirality.

DFT calculations

Based on our previous reports65,69, the arene may adopt two orientations during the C−H activation, and the alkyne may also coordinate from approaches toward the migratory insertion. These four combinations lead to four transition states (two leading to the (R) product and two to the (S) product). To gain deeper insights into the origins of the enantioselectivity, the key migratory insertion into the Rh−C bond was investigated by means of density functional theory (DFT) calculations (Fig. 8). For the [4 + 2] annulation with boron-based diyne 1, our computations show that insertion of the C–C triple bond into the Rh–C bond via the transition state (R)-TS1 is 1.4 kcal/mol lower in energy than via the transition state (S)-TS1 (Fig. 8a), which is in qualitative agreement with the experimentally observed enantioselectivity. The optimized geometries reveal the presence of π–π interaction between benzamide and boron-diyne moieties in both transition states. However, the orientation of the benzamide relative to the chiral ligand differs significantly. In transition state (S)-TS1, the repulsion between an OTIPS substituent of the chiral ligand and the OPiv group of the benzamide was observed with the O–O distance of 2.85 Å, which is absent in (R)-TS1, thus making (S)-TS1 higher in energy than (R)-TS1. For the reaction with BN–alkyne 44, the barrier of insertion of the C–C triple bond into the Rh–C bond via transition state (Ra)-TS2 is lower in energy than via transition state (Sa)-TS2 by 2.4 kcal/mol (Fig. 8b), which aligns well with the experimental results. Similarly, the orientation of indolylcarboxamide relative to the chiral ligand differs in the two transition states. The origin of the axial chirality is primarily attributed to the π–π interaction between indolylcarboxamide and chiral ligand in transition state (Ra)-TS2, which is absent in the (Sa)-TS2.

Fig. 8: DFT studies on the key migratory insertion step.
Fig. 8: DFT studies on the key migratory insertion step.The alternative text for this image may have been generated using AI.
Full size image

a transition states for the reaction with boron-diyne 1. b transition states for the reaction with BN–alkyne 44. Bond distances and energies are given in Å and kcal/mol, respectively.

Discussion

In summary, we have developed a highly efficient and redox-neutral method for synthesizing B-stereogenic and C−B axially chiral compounds using various (hetero)arenes and alkynyl organoboron reagents. The coupling system is initiated by Rh(III)-catalyzed C–H bond activation of the (hetero)arene substrate. The employment of a tetracoordinate gem-dialkynylboron with two classes of arenes afforded B-stereogenic compounds via [4 + 2] or [3 + 2] annulation. The employment of tricoordinate, sterically hindered boron-functionalized alkynes in [4 + 2] annulation with a 2-carboxamid-functinalized indole afforded C–B axially chiral biaryls via dynamic kinetic transformations of this class of alkyne. All the coupling reactions proceed under mild reaction conditions with good functional group tolerance, chemoselectivity, and enantioselectivity, requiring no additional stoichiometric amount of oxidant. The chiral-at-boron products exhibited variable configurational stability that is related to the tetrahedral character of the boron-stereogenic center. Moreover, the coupling system can be further applied to prepare chiral organoboron compounds bearing diverse drug-like molecular scaffolds. Photophysical properties have been explored for each category of products. We anticipate that this strategy may be applied to the asymmetric synthesis of other heteroatom stereocenters.

Methods

General procedure for the synthesis of 4–23

Conditions A

A scew-cap vial (8 mL) was charged with boron-diyne 1 (0.12 mmol, 1.2 equiv), (R)-Rh3 (4 mol%), AgBF4 (16 mol%), and CCA (50 mol%) in toluene (2 mL). The resulted mixture was kept at 0 °C for 15 min, to which was added nitrone 2 (0.10 mmol, 1.0 equiv). The reaction was maintained at 0 °C for 48 h. The reaction mixture was evaporated under vacuum and the residue was purified by preparative TLC to give the corresponding products 4–23.

General procedure for the synthesis of 24–42

Conditions B

A scew-cap vial (8 mL) was charged with boron-diyne 1 (0.12 mmol, 1.2 equiv), benzamide 3 (0.10 mmol, 1.0 equiv), (R)-Rh3 (4 mol%), PhCOOAg (50 mol%), and HOAc (0.20 mmol, 2.0 equiv) in toluene (2 mL) and the reaction mixture was stirred at 40 °C for 24 h. The reaction mixture was evaporated under vacuum and the residue was purified by preparative TLC to give the corresponding products 24–42.

General procedure for the synthesis of 45–61

Conditions C

A scew-cap vial (8 mL) was charged with BN-alkyne 44 (0.10 mmol, 1.0 equiv), indolecarboxamide 43 (0.15 mmol, 1.5 equiv), (R)-Rh4 (4 mol%), AgSbF6 (16 mol%), and Zn(OAc)2 (0.20 mmol, 2.0 equiv) in EA (2 mL) and the reaction mixture was stirred at 40 °C for 24 h under N2. The reaction mixture was evaporated under vacuum and the residue was purified by preparative TLC to give the corresponding products 45–61.